Allergic immune responses are biased toward the production of type-2 cytokines. We have identified new surface markers of a small subset of human natural killer (NK) cells that produce the type-2 cytokines, IL-4 and IL-13. In addition, we have shown that these type-2 NK cells are enriched in the lungs of atopic human subjects in response to allergenic challenge. Therefore, our data suggest that these cells may contribute to the inflammatory response at sites of allergenic insult, such as mucosal surfaces of the lung and gastrointestinal tract. Our discovery of better surface markers to delineate these cells allows us to better purify them and define their functions. In this application, we propose exploratory studies to significantly improve our understanding of the biology of type-2 NK cells. Specifically, we will 1) catalog receptors on the human type-2 NK cells and test their impacts on biological responses, and 2) use our knowledge in humans to characterize the type-2 NK cells in mice and test whether they can also respond to allergenic challenge in a mouse model of asthma. The findings will fill significant gaps in our understanding of environmental signals that regulate the functions of type-2 NK cells, and establish a mouse model for studying their in vivo functions. Improved understanding of these biological parameters will allow us to establish the roles of type-2 NK cells in the pathogenesis of localized allergic responses and infections, particularly in the respiratory and intestinal tracts. Future studies, based upon our findings, will be able to identify molecular targets to manipulate the functions of type-2 NK cells to improve human health. PUBLIC HEALTH RELEVANCE: to Public Health Natural killer (NK) cells are normal white blood cells that can stimulate innate immune responses. We have recently discovered surface markers to define a small subset of NK cells that can enter the lungs of human volunteers after exposure to an allergen. These cells are unique, since they can produce soluble factors that may contribute to allergic inflammation, and therefore, we will further study these cells in humans and mice to establishing their role in human health and disease.